PROJECT SUMMARY Depression and anxiety are commonly associated with Parkinson's disease (PD), and are often prevalent years before motor impairments upon which clinical diagnosis is made. The circuits and mechanisms underlying PD-related depression are unknown. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of heritable forms of PD. Disease progression in carriers of LRRK2 mutations, including depression, is similar to idiopathic cases suggesting a common mechanism. LRRK2 is enriched in dorsal striatum, the principal target of dopaminergic neurons that degenerate in PD, but paradoxically, its expression peaks developmentally during synaptogenesis, which may indicate that LRRK2 and PD-related mutant forms affect development of excitatory synaptic circuitry within the striatum. This suggests that altered neural circuit function conferred early in life by Lrrk2 mutation could render circuits vulnerable to PD-related depression and anxiety that manifest later in life. In support of this idea, our preliminary data show that in mice harboring the PD-related Lrrk2-G2019S gain-of-kinase function mutation, there is a significant increase in glutamatergic synaptic currents and abnormal spine morphology in developing striatal medium spiny neurons (MSNs) by postnatal day 21, a period that follows a burst in corticostriatal synaptogenesis. This is relevant because elevated glutamatergic signaling and spine abnormalities in ventral MSNs mediate elevated susceptibility to stress-induced depression-like behaviors. Consistent with this, we find in preliminary studies that G2019S mutant mice exhibit heightened sensitivity to social defeat stress, a model of stress-induced depression. Accordingly, our objective is to test the hypothesis that a PD-related Lrrk2 mutation that perturbs excitatory circuitry in striatal reward pathways early in life alters susceptibility to pro- depressive phenotypes by young adulthood. We will test this using mouse Lrrk2 knock-in models in an integrated combination of behavioral assays, whole-cell recording and pharmacological (small-molecule LRRK2 inhibitor) interventional approaches in vivo.